Throughout this specification, reference numbering is sometimes used to refer to the full citation for the references, which can be found in the “Reference Bibliography” after the Examples section. The disclosure of all patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety for all purposes.
In 2004, 186,772 women and 1,815 men were diagnosed with breast cancer, making it the second most common cancer in women. Conventional treatment includes surgery, chemotherapy, hormone therapy, and radiation. Breast conserving approaches have been increasingly used to treat invasive breast cancer. Historical data, however, have reported a 40% local recurrence rate after lumpectomy without radiotherapy1. Furthermore, the rate of local recurrence after mastectomy has been reported at 10-30%2. Local recurrence rate following lumpectomy without radiotherapy for ductal carcinoma in situ is as high as 63%, with invasive cancer occurring in over 36% of cases3,4, and a median recurrence between 2 and 6 years, depending on the initial stage of the resected tumor. Radiotherapy significantly reduces rate of local recurrence to 10% or less, but does not completely eliminate the risk of cancer5. Collectively, these data demonstrate the potential apparent normal breast possesses to harbor pre-malignant changes or very early malignancy at molecular level, and emphasize the insensitivity of the current strategies to detect disease at an early molecular stage, even in patients known to be at high-risk. The potential benefit of a molecular signature as an indication of risk for subsequent development of breast cancer would, therefore, be very useful in screening applications.
Currently, it is estimated that false negatives and new cancers previously screened as negative may amount to 2-4% of the new cancer cases following breast biopsy6. Determination of molecular markers of malignancy in histologically normal breast may improve the potential for breast biopsy to identify at-risk patients, refine the current practice of intra-operative assessment of margins of the resected breast tissues based on histology alone, and may prove useful in guiding treatment choices after lumpectomy. For example, it is clear that not all patients require or benefit from post-lumpectomy radiotherapy, which often leads to considerable cosmetic defects in the residual breast.
Accordingly, there is a need for the ability for to predict which individuals, who have histologically normal breast tissue, will likely develop breast cancer, or breast cancer recurrence, or metastasis of breast cancer. The ability for physicians and/or others of skill in the art allows for personalized treatment of patients and avoids unnecessary treatments that are not beneficial to the patient's health.
The invention provides for, inter alia, malignancy-risk gene signatures that predict the risk of developing breast cancer, the recurrence of breast cancer, and/or the metastasis of breast cancer; methods of using such signatures, and kits containing arrays of malignancy-risk gene signatures. Thus, one objective of the invention was to establish high cancer-risk gene signatures in histologically normal breast tissues obtained from patients with invasive breast cancer. Other objectives are described in greater detail infra.
As detailed further in the Examples, outlier gene signatures were derived to assess cancer risk from the 143 histologically normal breast tissues derived from patients who underwent mastectomy for breast carcinoma. Up to four normal breast samples, adjacent to an invasive ductal carcinoma, were obtained from each patient. Validation results indicated that the outlier gene signature had multiple predictive properties, including potential to predict cancer risk, disease progression, and metastasis. Since the outlier genes were highly associated with cell proliferation, it is conceivable that these proliferation genes may have a role in the earliest stages of breast cancer development and subsequent progression.
These signatures have numerous clinical applications including, but not limited to, assessing risk of breast cancer development following routine breast biopsy, assessing the need for adjuvant radiotherapy after lumpectomy, and determining the need for completion mastectomy following lumpectomy for the breast cancer patient and other treatment plans that are personalized for the patient and thus, fulfill several needs in this field.